Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson's disease

Abstract

Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects following ischemia, suggesting that VEGF may potentially be applied as a neuroprotective agent for the treatment of other neurological diseases. In this study, we investigated the neuroprotective capacity of VEGF in a model of Parkinson's disease. VEGF was found to be neuroprotective against cell death of primary E14 murine ventral mesencephalic neurons induced by 6-hydroxydopamine (6-OHDA) treatment in vitro. Further, rats receiving a continuous infusion of VEGF into the striatum via encapsulated hVEGF-secreting cells (baby hamster kidney-VEGF) displayed a significant decrease in amphetamine-induced rotational behavior and a significant preservation of tyrosine hydroxylase-positive neurons and fibers compared with control animals. VEGF likely functions via direct mechanisms by signaling through the neuropilin receptor expressed upon dopaminergic neurons in response to 6-OHDA treatment. Further, VEGF is likely to promote neuroprotection indirectly by activating the proliferation of glia and by promoting angiogenesis. Our results support a potential neuroprotective role for VEGF in the treatment of Parkinson's disease.

Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease

“…5B). Based on these present results and those from previous studies (Maruyama et al, 2001(Maruyama et al, , 2002Yasuhara et al, 2004Yasuhara et al, , 2005, 40 M 6-OHDA for 24 h was used in subsequent studies. In addition, immunocytochemical evaluation of SH-SY5Y cells revealed that most cells were well stained with antibodies against MAP2, TH, and human nuclei and rarely stained with anti-nestin antibody, indicating the dopaminergic neuronal phenotype of this cell line (Fig.…”

“…At 2 d after culture, medium was exchanged to DMEM with 5% FBS as a control or mixture of DMEM with 10% FBS and preserved CM (1:1). Ten minutes later, 6-OHDA was added to the final concentration of 40 M as per our previous studies and those of others (Maruyama et al, 2001(Maruyama et al, , 2002Yasuhara et al, 2004Yasuhara et al, , 2005. At 24 h after 6-OHDA treatment, the cultures were examined using MTT assay (Promega) or immunocytochemically (see below).…”

“…To clarify whether neuroprotective effects of the CM with SCF involved anti-apoptotic effects, a modified method for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, (TUNEL) (Roche, Mannheim, Germany) was performed to evaluate apoptotic cell death, as described in our previous report (Yasuhara et al, 2004). At 12 h after 6-OHDA treatment, cultured cells with or without CM treatment were fixed with 4% PFA for 20 min and then washed with PBS (supplemental Fig.…”

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

“…These studies demonstrate that the neuroprotective properties of DPI and apocynin are not due to inhibition of microglial NADPH oxidase, but rather are due to inhibition of endogenously expressed NADPH oxidase. In animal studies, DPI and apocynin protect against global cerebral ischemia (Wang et al, 2006), and rotenone- (Gao et al, 2003a), paraquat- (Purisai et al, 2006), 6-OHDA- (Yasuhara et al, 2004), MPTP- (Gao et al, 2003b) and IFN-gamma/LPS- (Hirsch et al, 2003a) induced dopaminergic degeneration. In these studies, the neuroprotective properties of apocynin and DPI were associated with inhibition of microglial NADPH oxidase activity, but the role of neuronal NADPH oxidase was not investigated.…”

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

“…Direct intra-striatal infusion and implantation of capsules containing VEGF (35) and gene transfer of VEGF using adenoassociated viral vectors (36) have also been demonstrated to rescue DAergic neurons from 6-hydroxydopamine toxicities in rodent models of PD. In our studies, we utilized a mouse model of pan-neuronal overexpression of VEGF to determine whether VEGF would also provide protection against MPTP toxicity in our model.…”